Pancreatic and duodenal homeobox protein 1 (Pdx-1) maintains endoplasmic reticulum calcium levels through transcriptional regulation of sarco-endoplasmic reticulum calcium ATPase 2b (SERCA2b) in the islet ß cell.

Although the pancreatic duodenal homeobox 1 (Pdx-1) transcription factor is known to play an indispensable role in ß cell development and secretory function, recent data also implicate Pdx-1 in the maintenance of endoplasmic reticulum (ER) health. The sarco-endoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) pump maintains a steep Ca(2+) gradient between the cytosol and ER lumen. In models of diabetes, our data demonstrated loss of ß cell Pdx-1 that occurs in parallel with altered SERCA2b expression, whereas in silico analysis of the SERCA2b promoter revealed multiple putative Pdx-1 binding sites. We hypothesized that Pdx-1 loss under inflammatory and diabetic conditions leads to decreased SERCA2b levels and activity with concomitant alterations in ER health. To test this, siRNA-mediated knockdown of Pdx-1 was performed in INS-1 cells. The results revealed reduced SERCA2b expression and decreased ER Ca(2+), which was measured using fluorescence lifetime imaging microscopy. Cotransfection of human Pdx-1 with a reporter fused to the human SERCA2 promoter increased luciferase activity 3- to 4-fold relative to an empty vector control, and direct binding of Pdx-1 to the proximal SERCA2 promoter was confirmed by chromatin immunoprecipitation. To determine whether restoration of SERCA2b could rescue ER stress induced by Pdx-1 loss, Pdx1(+/-) mice were fed a high-fat diet. Isolated islets demonstrated an increased spliced-to-total Xbp1 ratio, whereas SERCA2b overexpression reduced the Xbp1 ratio to that of wild-type controls. Together, these results identify SERCA2b as a novel transcriptional target of Pdx-1 and define a role for altered ER Ca(2+) regulation in Pdx-1-deficient states.

Long-term maintenance of immediate or delayed extinction is determined by the extinction-test interval.

Short acquisition-extinction intervals (immediate extinction) can lead to either more or less spontaneous recovery than long acquisition-extinction intervals (delayed extinction). Using rat subjects, we observed less spontaneous recovery following immediate than delayed extinction (Experiment 1). However, this was the case only if a relatively long extinction-test interval was used; a relatively short extinction-test interval yielded the opposite result (Experiment 2). Previous data appear consistent with this observation suggesting that, although delayed extinction appears more beneficial in the short term, immediate extinction may have more favorable long-term effects. These observations may have important implications for attenuation of relapse in clinical situations.

Translational implications of the ß-cell epigenome in diabetes mellitus.

Diabetes mellitus is a disorder of glucose homeostasis that affects more than 24 million Americans and 382 million individuals worldwide. Dysregulated insulin secretion from the pancreatic ß cells plays a central role in the pathophysiology of all forms of diabetes mellitus. Therefore, an enhanced understanding of the pathways that contribute to ß-cell failure is imperative. Epigenetics refers to heritable changes in DNA transcription that occur in the absence of changes to the linear DNA nucleotide sequence. Recent evidence suggests an expanding role of the ß-cell epigenome in the regulation of metabolic health. The goal of this review is to discuss maladaptive changes in ß-cell DNA methylation patterns and chromatin architecture, and their contribution to diabetes pathophysiology. Efforts to modulate the ß-cell epigenome as a means to prevent, diagnose, and treat diabetes are also discussed.